https://orcid.org/0000-0003-2081-8558
Abstract
SSc is an auto-immune disease characterized by life-threatening manifestations such as lung fibrosis or pulmonary arterial hypertension. Symptoms with a detrimental impact on quality of life are also reported and sicca syndrome (xerostomia, xeropthalmia) is present in up to 80% of patients with SSc. Sicca syndrome can occur in the absence of overlap with Sjögren’s disease and recent studies highlight that fibrosis of minor and major salivary glands, directly linked to the pathogenesis of SSc, could be a major contributor of xerostomia in SSc. This narrative review provides an overview of the clinical presentation, diagnostic strategies, management and future perspectives on sicca syndrome in patients with SSc.
Manifestations of SSc include disabling daily symptoms such as sicca syndrome.
SSc-related fibrosis of salivary glands or associated Sjögren’s disease can induce sicca syndrome in SSc.
Sicca syndrome in SSc assessment combines subjective and objective clinical and paraclinical findings (imaging, histological data).
Introduction
SSc (also called scleroderma) is a rare autoimmune disorder driven by a physiopathological triad including inflammation, vasculopathy and fibrosis of skin and internal organs [1]. SSc has the highest individual mortality of all rheumatic diseases. Pulmonary fibrosis is among the major causes of SSc-related death [2]. The management of fibrotic manifestations of the disease remains challenging but other SSc-related symptoms may be unfairly neglected. Upper gastrointestinal (GI) involvement and oro-facial manifestations such as sicca syndrome are reported in up to 80% of patients with SSc [3]. Recent histological and ultrasonographic data suggest that sicca syndrome could result from SSc-related fibrosis of salivary glands [4]. Sicca syndrome in SSc could thus be the direct consequence of scleroderma or an overlap syndrome with SS [5, 6].
Literature regarding sicca syndrome is mainly based on primary SS (pSS). Only a few studies have focused on the specificities of SSc-related sicca syndrome, in terms of clinical presentation, impact on health-related quality of life (QoL), diagnostic strategies and management. Data on SSc patients suggest that oro-facial manifestations of the disease, including sicca syndrome, may directly impair QoL of SSc patients [7]. A recent systematic review comparing oral-health-related quality of life (OHRQoL) of patients with rheumatic diseases with healthy controls confirmed the severe impact of SSc on this parameter [8]. Drug regulatory agencies have emphasized the importance of patient reported outcomes and QoL assessment as cornerstones of disease evaluation. Potential neglected issues such as sicca syndrome may thus deserve further attention in the overall management of SSc patients. New diagnostic tools in pSS, such as US evaluation of major salivary glands, may impact the diagnostic strategies of SSc-related sicca syndrome and change our view on the pathogenesis of this manifestation of the disease. This narrative review provides an overview of the clinical presentation, diagnostic strategies, management and future perspectives on sicca syndrome in patients with SSc.
We identified references through search of PubMed with the search terms (‘systemic sclerosis’ OR ‘Scleroderma’ OR ‘CREST’) AND (‘sicca syndrome’ OR ‘reduced salivary flow’ OR ‘Sjögren’s’) from inception of the database until December 2020 (1561 abstracts). We also identified articles through hand search in the references from the full texts identified, searches of the authors’ own files, conference abstracts (including EULAR congress) and updated reference list using the same search strategy in 2021 and 2022. The final reference list was generated on the basis of its relevance for the topic. In accordance with recommendations for the writing of a narrative review in rheumatology [9], in depth discussion among co-authors and experts in the field from different centres enriched the manuscript as well as the reference list and provided perspectives and a research agenda for the future.
Prevalence of sicca syndrome in SSc and impact on health-related quality of life
Prevalence
SSc includes a wide range of oro-facial manifestations [10, 11]. These manifestations notably include reduced oral opening in 85% of the patients, telangiectasias in 92% [12], and decreased lacrimal and salivary secretion [13]. The exact prevalence of sicca syndrome in SSc varies according to inclusion criteria and definition of sicca symptoms in these studies. Table 1 provides the main results on outcomes and prevalence in major studies exploring sicca syndrome in SSc. Current classification of pSS is based on 2016 ACR–EULAR criteria and 2002 American–European Consensus Group (AECG) classification criteria [14, 15]. Based on the AECG criteria, the prevalence of overlap with pSS was 12% in two Italian and French SSc cohorts [16]. A study comparing 2217 patients with SSc and 6485 controls from Taiwan’s Registry of Catastrophic Illness database and National Health Insurance Research Database revealed higher risk of SS in the SSc population after adjusting for age, sex and various autoimmune diseases (hazard ratio: 5.98, 95% CI: 4.79, 7.47; P < 0.001) [17]. The prevalence of reported subjective xerostomia varies from 52.5% to 80% in the literature [10, 13, 18]. The prevalence of sicca syndrome in SSc reached 66% when considering objective functional tests (Schirmer’s test or salivary flow rate) in recent studies [19]. Sicca symptoms may equally affect patients with limited cutaneous SSc and diffuse cutaneous SSc according to Leroy’s classification [19]. A lower prevalence in sine scleroderma patients has been reported [18]. Regarding autoantibody status, sicca syndrome was more frequent in SSc patients with positive ACA [20].
Main studies exploring sicca syndrome in patients with SSc
| Article | Population | Prevalence for subjective Sicca symptoms (self-reported symptoms) | Prevalence for objective Sicca symptoms | Histological findings | Diagnosis of overlap with pSS |
|---|---|---|---|---|---|
| Avouac et al. 2006 [22] | 133 SSc | 68% | Schirmer <5 mm 46% |
| 14% AECG criteria |
| Kobak et al. 2013 [21] | 118 SSc | 71.2% (sicca questionnaire) |
| 34% Grade 3/4 Chisholm | 33.9% AECG criteria |
| Kucuk et al. 2018 [52] | 26 SSc | NA | NA |
| NA |
| Couderc et al. 2020 [41] | 25 SSc |
| Schirmer <5 mm 53% | NA | NA |
| Lee et al. 2020 [42] | 62 SSc, |
| NA | NA | NA |
| Can et al. 2021 [51] | 102 SSc | 75% |
|
| 35.3% fulfilling AECG criteria |
| Article | Population | Prevalence for subjective Sicca symptoms (self-reported symptoms) | Prevalence for objective Sicca symptoms | Histological findings | Diagnosis of overlap with pSS |
|---|---|---|---|---|---|
| Avouac et al. 2006 [22] | 133 SSc | 68% | Schirmer <5 mm 46% |
| 14% AECG criteria |
| Kobak et al. 2013 [21] | 118 SSc | 71.2% (sicca questionnaire) |
| 34% Grade 3/4 Chisholm | 33.9% AECG criteria |
| Kucuk et al. 2018 [52] | 26 SSc | NA | NA |
| NA |
| Couderc et al. 2020 [41] | 25 SSc |
| Schirmer <5 mm 53% | NA | NA |
| Lee et al. 2020 [42] | 62 SSc, |
| NA | NA | NA |
| Can et al. 2021 [51] | 102 SSc | 75% |
|
| 35.3% fulfilling AECG criteria |
AECG: American–European Consensus Group; FS: focus score; NA: not available; pSS: primary Sjögren’s syndrome; USFR: unstimulated flow rate; XPM: xerophthalmia; XSM: xerostomia.
Main studies exploring sicca syndrome in patients with SSc
| Article | Population | Prevalence for subjective Sicca symptoms (self-reported symptoms) | Prevalence for objective Sicca symptoms | Histological findings | Diagnosis of overlap with pSS |
|---|---|---|---|---|---|
| Avouac et al. 2006 [22] | 133 SSc | 68% | Schirmer <5 mm 46% |
| 14% AECG criteria |
| Kobak et al. 2013 [21] | 118 SSc | 71.2% (sicca questionnaire) |
| 34% Grade 3/4 Chisholm | 33.9% AECG criteria |
| Kucuk et al. 2018 [52] | 26 SSc | NA | NA |
| NA |
| Couderc et al. 2020 [41] | 25 SSc |
| Schirmer <5 mm 53% | NA | NA |
| Lee et al. 2020 [42] | 62 SSc, |
| NA | NA | NA |
| Can et al. 2021 [51] | 102 SSc | 75% |
|
| 35.3% fulfilling AECG criteria |
| Article | Population | Prevalence for subjective Sicca symptoms (self-reported symptoms) | Prevalence for objective Sicca symptoms | Histological findings | Diagnosis of overlap with pSS |
|---|---|---|---|---|---|
| Avouac et al. 2006 [22] | 133 SSc | 68% | Schirmer <5 mm 46% |
| 14% AECG criteria |
| Kobak et al. 2013 [21] | 118 SSc | 71.2% (sicca questionnaire) |
| 34% Grade 3/4 Chisholm | 33.9% AECG criteria |
| Kucuk et al. 2018 [52] | 26 SSc | NA | NA |
| NA |
| Couderc et al. 2020 [41] | 25 SSc |
| Schirmer <5 mm 53% | NA | NA |
| Lee et al. 2020 [42] | 62 SSc, |
| NA | NA | NA |
| Can et al. 2021 [51] | 102 SSc | 75% |
|
| 35.3% fulfilling AECG criteria |
AECG: American–European Consensus Group; FS: focus score; NA: not available; pSS: primary Sjögren’s syndrome; USFR: unstimulated flow rate; XPM: xerophthalmia; XSM: xerostomia.
Studies exploring the correlation between sicca symptoms and histological findings have demonstrated a lack of concordance between subjective sicca symptoms and histological sialadenitis. In a monocentric cross-sectional study including 118 SSc patients, sicca symptoms were reported in 71% of SSc patients and grade 3 or 4 sialadenitis was only observed on minor salivary gland biopsy in 33% of the cases [21]. In a multicentric study including 133 SSc patients, the prevalence of subjective sicca symptoms was 64%. Histological data revealed fibrotic lesions in 55% of cases although only 19 patients (19%) fulfilled the AECG criteria for pSS [22]. These results strengthen the hypothesis that beyond pSS-related sialadenitis, a specific impact of SSc on salivary glands may participate in sicca syndrome.
Impact on everyday life and measured quality of life
Reduction of salivary flow can lead to several complications impacting everyday life. Patients may experience difficulties in eating dry food, wearing dentures for a long period of time, or speaking without taking frequent sips of water [23]. Changes in taste and difficulty eating spicy or acidic food may result in reduced food intake and denutrition. Increased oral Candida infection and high rate of caries are also classically reported [24]. An observational study including 35 SSc patients suggested an association between sicca syndrome and Helicobacter pylori infection since 78% of the patients with sicca syndrome had a concomitant H. pylori infection, compared with 42% in those without. Altered peristalsis and reduced salivary clearance were suggested as potential causes to explain this association [25].
Several studies have specifically focused on the impact of oro-facial manifestations and sicca syndrome on health-related QoL in SSc [8]. Xerostomia is among the most bothersome symptoms reported by SSc patients [18]. A systematic review on OHRQoL demonstrated that Oral Health Impact Profile 49 (OHIP 49) of SSc patients was lower than for healthy individuals. The Canadian SSc Oral Health Study I specifically explored the association between oral manifestations of the disease and OHRQoL, showing independent association of SSc with reduced salivary flow and altered OHRQoL [26]. The Canadian SSc Oral Health Study II also demonstrated an association between Oral and Global QoL in SSc [7]. However, the OHRQol score did not correlate with the severity of organ involvement in SSc patients, suggesting that all SSc subsets could be considered regardless of the severity of SSc-related visceral manifestations [26]. In addition to classical oral manifestations, ocular and vaginal symptoms are also reported. Although SSc patients more frequently complained of sexual dysfunction compared with the general population, only scarce data are available on the specific impact of sicca syndrome on sexuality in SSc [27]. Tristano et al. mentioned a higher frequency of vaginal dryness or tightness, and dyspareunia in patients with SSc [28].
Current reference standards for the evaluation of sicca syndrome in patients with SSc
Diagnostic approach
Screening and clinical assessment
Clinical screening is an important step as patients with xerostomia. Although subjective clinical complaints are predictive of reduced salivary flow on objective evaluations, there is no concordance between objective and subjective tests. Only 68% of patients with self-reported sicca symptoms show decreased salivary or lachrymal flow on objective tests [19].
The Mouth Handicap In Systemic Sclerosis (MHISS) scale can be used for screening oral sicca symptoms, among the 12 items included in this scale, two are directly related to sicca syndrome (‘My mouth is dry’; ‘I must drink often’…). The GIT SCTC UCLA (Gastrointestinal Tract Instrument Scleroderma Clinical Trial Consortium from University of California, Los Angeles) scale does not include sicca syndrome and is not appropriate for such a screening. Sialometry is the reference standard to objectively confirm the presence of xerostomia. A salivary flow above 0.1 ml/min is considered as normal [29].
Xerophthalmia is the other hallmark clinical manifestation of sicca syndrome. Patients may report burning or soreness of the eyes and increased sensitivity to light. The Schirmer test is an accessible and objective instrument to diagnose impaired tear secretion (wetting <5 mm of a strip of sterile paper placed for 5 min in contact with the ocular surface) [30]. Other objective methods include corneal staining with fluorescein, rose bengal or lissamine green, which require eye examination by an ophthalmologist [31]. Non-invasive film tear break-up time and tear film lipid layer thickness are other evaluation techniques for eye dryness [32].
Histological considerations of minor salivary gland biopsy
As an overlap with pSS may concern up to 20% of SSc patients, the diagnosis of sialadenitis based on histological evaluation of salivary glands is one of the cornerstones of sicca syndrome assessment. Minor salivary gland biopsy (mSGB) is one of the two key criteria for the diagnosis of pSS in the revised 2016 ACR/EULAR criteria. This histological criterion is defined by lymphocytic sialadenitis with a focus score >1, and has a weighting of 3 points amongst the 4 points mandatory for the classification of SS. Minor salivary gland biopsy is still considered an invasive procedure as suggested by a single centre study evaluating 502 minor salivary gland biopsies in which 12% of adverse events were reported, paresthaesia and external haematoma being the most common complications [33]. In a meta-analysis from 2014, over 1–5% adverse events were considered serious and persistent, suggesting that alternative non-invasive options are warranted [34].
Imaging techniques under investigation for assessment of major salivary gland involvement
US evaluation
US evaluation of major salivary glands is a low cost, non-invasive, non-irradiating, easy to use tool that is currently being evaluated for the diagnosis of pSS [35]. Ultrasound descriptions report an inhomogeneous appearance of the tissue, hypoechoic areas, potentially organized in cystic areas in patients with pSS [36, 37].
Ultrasound abnormalities of major salivary glands correlate with histological findings on mSGB. A retrospective analysis of 85 patients with suspected SS showed that salivary gland ultrasound had a positive predictive value of 85% and a negative predictive value of 96% using mSGB as reference standard [38]. In comparison with sialography and sialendoscopy, US showed higher sensitivity for the diagnosis of pSS [39]. Including salivary gland ultrasonography parameters in the ACR/EULAR 2016 improved sensitivity from 77.9% to 85.7% [37]. A recent OMERACT initiative has proposed consensus criteria for the evaluation of major salivary gland involvement in pSS (Figs 1 and 2). These criteria include four grades: grade 0, normal parenchyma; grade 1, minimal change (mild inhomogeneity without anechoic/hypoechoic areas); grade 2, moderate change (moderate inhomogeneity with focal anechoic/hypoechoic areas but surrounded with normal tissue); and grade 3, severe change diffuse inhomogeneity with anechoic/hypoechoic areas occupying the entire gland surface but surrounded with no normal tissue. Based on video-clip assessment, intra-observer Cohen’s kappa was 0.81 and inter-reader reliability was good (Light’s kappa 0.66) [40].
OMERACT score for ultrasound assessment of parotid glands in patients with SSc
(A) Grade 0, normal parenchyma. (B) Grade 1, minimal change: mild inhomogeneity without anechoic/hypoechoic areas. (C) Grade 2, moderate change: moderate inhomogeneity with focal anechoic/hypoechoic areas but with preserved surrounding normal tissue. (D) Grade 3, severe change: diffuse inhomogeneity with anechoic/hypoechoic areas occupying the entire gland surface but without surrounding normal tissue or only fibrotic aspect with a parotid parenchyma indistinguishable from the adjacent tissue. (E) Ultrasound view of the parotid glands (OMERACT grade 3). Grade 3 is characterized by the absence of healthy parenchyma. Hyperechoic fibrotic bands (blue dashed lines) are key features of OMERACT grade 3 in SSc patients.
OMERACT score for ultrasound assessment of submandibular glands in patients with SSc
(A) Grade 0, normal parenchyma. (B) Grade 1, minimal change mild inhomogeneity without anechoic/hypoechoic areas. (C) Grade 2, moderate change: moderate inhomogeneity with focal anechoic/hypoechoic areas but with preserved surrounding normal tissue. (D) Grade 3, severe change: diffuse inhomogeneity with anechoic/hypoechoic areas occupying the entire gland surface but without surrounding normal tissue or only fibrotic aspect with a submandibular parenchyma indistinguishable from the adjacent tissue. (E) Ultrasound view of the parotid glands (OMERACT grade 3). Grade 3 is characterized by the absence of healthy parenchyma. Hyperechoic fibrotic bands (blue dashed lines) are key features of OMERACT grade 3 in SSc patients.
The relevance of US evaluation of major salivary gland involvement in SSc is still to be determined. Two main US features of major salivary gland are classically described in patients with SSc: hyperechoic bands suggestive of glandular fibrosis and pseudo-cystic areas characterizing glandular degeneration [4]. A prospective single-centre study comparing ultrasound data from 25 SSc, 48 pSS and 35 controls reported that 25% of SSc patients had inhomogeneity of major salivary glands on US evaluation [41]. Using the OMERACT parameters, an observational study comparing 62 SSc, 59 pSS and 43 idiopathic sicca syndrome demonstrated that 51.6% of SSc patients had an OMERACT grade ≥2 [42]. In this study, total US scores based on the OMERACT criteria were higher in SSc and pSS than in patients with idiopathic sicca syndrome. Total OMERACT grade was higher in parotid glands of pSS patients in comparison with SSc and this difference was not reported for submandibular glands. No difference in fibrosis grades was observed between SSc and pSS groups. Within SSc patients, higher OMERACT scores (≥2) were associated with limited cutaneous SSc, higher prevalence of subjective sicca symptoms, and higher prevalence of ACA, anti-SSA and anti-SSB. To our knowledge, there is no study comparing ultrasound parameters with histological data in scleroderma patients. An ongoing multicentric observational study may help to clarify this issue in the future (NCT04001556, clinicaltrials.gov).
Other imaging techniques of major salivary glands
Specific MRI sequences (MR sialography, STIR, T2–3D-DRIVE) identifying fat deposits in the parotid gland along with the detection of peripheral duct dilation have shown promising diagnostic performances in pSS. A cross-sectional study including 107 patients demonstrated that MRI and MR sialography used together had a positive diagnosis rate of 96.8% for pSS [43]. The relevance of these technique in SSc is still to be determined.
Salivary gland scintigraphy is a non-invasive, well tolerated, reproducible technique that predicts salivary gland functioning in pSS. This technique notably correlated with clinical and histological features [44, 45]. An observational study including 405 patients with pSS showed that more severe scintigraphy stages were associated with a higher risk of B-cell lymphoma and a lower survival rate [46]. Salivary gland scintigraphy could be more sensitive than MR sialography for the diagnosis of pSS, whereas MR sialography showed a higher specificity and positive predictive value [47]. No data are available in SSc to date. The 18F-fluorodeoxyglucose PET technique could help in the assessment of disease activity based on the EULAR Sjögren's syndrome disease activity index (ESSDAI) in pSS, but its relevance in SSc-related sicca syndrome is unknown [48].
Other radiological considerations suggestive of pSS in patients with SSc
Chest HRCT-scan is recommended in all SSc patients for initial screening of SSc-interstitial lung disease (ILD). The main CT findings consistent with SSc-ILD are non-specific interstitial pneumonia or usual interstitial pneumonia patterns. By contrast, parenchymal cysts or peribronchiolar micronodular infiltrate consistent with a tree-in-bud pattern are suggestive of pSS and uncommon in SSc-ILD [49]. Therefore, such imaging findings in SSc should lead to careful detection of clinical and biological parameters that could confirm an overlap with pSS.
Specific histological and phenotypic considerations in SSc-related sicca syndrome
Histological considerations regarding minor salivary glands in SSc
Extracellular matrix accumulation is one of the key aspects of SSc pathogenesis [50]. Fibrosis of the minor salivary glands may therefore differentiate SSc-related sicca syndrome and pSS. In Avouac’s study evaluating 133 SSc patients, 20% of minor salivary gland biopsies showed a focus score >1 and 55% showed glandular fibrosis. Fibrotic lesions were defined as fibrous tissue with secreting fibroblasts surrounding the acini and located around capillaries and excretory ducts [22]. Another study evaluating mSGB from 102 SSc patients reported lymphocytic sialadenitis in 45% of the cases. In the subgroup of SSc patients with objective sicca syndrome, glandular fibrosis was reported in 80% of mSGB (those graded mild, moderate and severe fibrosis made up 67%, 24% and 9%, respectively) [51]. A cross-sectional study comparing 43 pSS and 26 SSc demonstrated that plasma cell foci were more frequent in pSS compared with SSc. Further studies are needed to fully understand the specific role of these plasma cell aggregates on minor salivary gland biopsy in pSS [52]. Histological patterns in SSc patients are presented in Fig. 3.
Histological patterns in labial salivary glands (haematoxylin and eosin staining) from patients with systemic sclerosis and sicca syndrome (xerostomia)
(A) Normal glandular structure and normal acini (white stars). (B) Lymphocytic sialadenitis with focus score >1. (C) Mild interstitial fibrosis (arrows) with normal (white stars) and/or atrophic acini (black stars), without lymphocytic sialadenitis. (D) Presence of lymphocytic sialadenitis with focus score >1 associated with interstitial fibrosis.
Clinical phenotype of SSc patients with SSc-related sicca syndrome or overlap syndrome with pSS
Although some work has suggested that eye dryness was associated with more severe skin involvement in SSc [32], in the majority of available studies, SSc patients with associated sicca syndrome tend to have a milder disease phenotype. In a population of 118 patients with SSc, compared with SSc alone, overlap with SS was associated with less pulmonary hypertension and less diffuse lung involvement [21]. The Canadian Systemic Sclerosis Oral Health Study III, a cross-sectional study including 163 SSc patients from the Canadian Scleroderma Research Group cohort, revealed that objective decreased saliva production was associated with pSS (β = −43.32; 95% CI: −80.89, −5.75), but not with SSc severity according to the modified Medsger severity scale (β = 2.51; 95% CI: −8.75, 3.73) [53]. A retrospective multicentric study comparing 27 SSc patients with associated SS, 202 pSS and 94 SSc patients demonstrated that SSc patients with associated SS and pSS had similar characteristics regarding sicca manifestations, presence of anti-SSA, anti-SSB or histological grade on minor salivary glands. Among SSc patients, those without associated SS tended to have less frequent SSc-related pulmonary manifestations [54]. Another retrospective monocentric study confirmed that SSc patients with pSS overlap had milder phenotype especially considering the prevalence of pulmonary arterial hypertension. Among SSc patients with SS overlap, the authors highlighted a specific subgroup characterized by a positivity for ACA and limited cutaneous involvement. This subgroup of patients with ‘ACA-positive limited SSc overlap syndrome’ showed an increased risk of non-Hodgkin’s lymphoma (six cases in overlap subset, one case in SSc subgroup, P = 0.002). This higher prevalence of non-Hodgkin’s lymphoma strengthens the relevance of identifying pSS among SSc patients to properly adapt management and follow-up [55].
A specific subset of patients with pSS and positivity for SSc-specific autoantibodies (including anti-centromere antibodies) but without SSc has also been recently explored. These data highlighted that strong titres of SSc-specific antibodies in patients with sicca complaints was associated with abnormal histopathological findings on biopsies of minor salivary glands [56]. Whether this population of patients with sicca symptoms corresponds to a specific subgroup of pSS or a pre-scleroderma condition (early or very early SSc) overlapping with pSSc is still to be determined. Interestingly, a recent ultrasound study of pSS (excluding patients with SSc) suggested that in this population of patients fulfilling the 2002 AECG classification criteria for pSS, positivity for anti-centromere antibodies was associated with less severe involvement of major salivary glands on ultrasound evaluation [57]. These data may suggest that an immunological continuum may exist between pSS and SSc patients with anti-centromere antibodies [58].
Therapeutic approaches and management of sicca syndrome in patients with SSc
Recommendations for the management of oral manifestations in patients with SSc were proposed in 2011 based on literature review and expert agreement [23]. A multidisciplinary approach is an important part of sicca syndrome management in SSc. Occupational therapists, physical therapists, nutrition specialists, dentists and maxillofacial surgeons should participate in this multidisciplinary management [23].
Non-pharmacological measures
Non-pharmacological measures are the cornerstone of sicca syndrome management. Education and nutritional measures include decreasing alcohol or spiced food consumption, which participate in mouth dryness. Discontinuation of treatments with anticholinergic properties (i.e. antidepressant or anti-histaminic drugs), which can worsen or induce sicca syndrome, should be considered [23]. Other non-pharmacological measures include gustatory stimulants (sugar-free acidic candies, lozenges and xylitol) as well as mechanical stimulants (sugar-free chewing gum) [59]. Facial massage of major-salivary glands could also improve salivary flow.
Pharmacological measures
There is no specific study focusing on the pharmacological treatment of sicca syndrome in SSc. Therapies are divided into agents used as topical replacement of deficient secretions (artificial tears, artificial saliva) and those stimulating muscarinic receptors (pilocarpine) with subsequent increase of aqueous secretions. The 2019 EULAR recommendations for the management of pSS highlight that symptomatic treatment based on topicals with minimal adverse effects should be preferred [59]. Recommendations for oral care in SSc insist on maintaining oral hydration with water in addition to sialological treatments (tincture of pilocarpine 40 drops/day; pilocarpine 5 mg, 3 caps/day; and anetholtrithione 3 caps/day) or salivary spray substitute [23]. EULAR guidelines recommend the use of sialological treatments in patients refractory to non-pharmacological measures [59]. Administration of oral pilocarpine in 31 patients with subjective sicca syndrome (reporting dry mouth) showed an objective increase in salivary secretion in 21 patients and a subjective improvement in 27 of 31 patients after 5 months of treatment in a double blind trial [60]. Oral administration of pilocarpine, in 15 patients diagnosed with pSS according to AECG criteria, showed an improvement in ocular symptoms (burning and foreign body, dryness) and a significant increase in goblet cells (cells specialized in mucous secretion) in a 2-month prospective study [61].
An interaction between the activation of glandular epithelial cells that induces B cell activation through plasma mediators, including BAFF (B-cell activating factor), participates in the pathophysiology of pSS. As B cells are also involved in the pathogenesis of SSc, the rationale for targeting this cell population may also be relevant in SSc [62]. Rituximab, a monoclonal antibody targeting the B cell marker CD20, reduced global disease burden in patients with pSS [63]. A pilot study comparing the effects of rituximab and placebo in 17 patients with pSS showed a significant decrease in fatigue (>20% reduction of visual analogue scale [VAS] vs baseline), but there was no significant change of salivary flow [63]. A phase III randomized, placebo-controlled trial comparing rituximab and placebo in 120 patients with pSS failed to demonstrate the efficacy of active therapy on at least two of four VASs (global disease, pain, fatigue and dryness) [64]. The effect of rituximab on SSc-associated sicca syndrome is still to be determined.
Other biologics targeting B cells such as belimumab have been evaluated in pSS and are currently being evaluated in SSc [62]. The phase II BELISS study compared the effect of belimumab vs placebo in pSS. The primary end point evaluated at week 28 was improvement in two of the five following items: ≥30% reduction in dryness score on a VAS; ≥30% reduction in fatigue score on a VAS; ≥30% reduction in musculoskeletal pain score on a VAS; ≥30% reduction in systemic activity score on a VAS assessed by the physician; and/or ≥25% reduction in serum levels of any of the B cell activation biomarkers free light chains of immunoglobulin, β2-microglobulin, monoclonal component, cryoglobulin and IgG, or ≥25% increase in C4 level. Sixty percent of the patients showed an improvement in at least two of these five criteria. There was a significant improvement in ESSDAI, fatigue and pain in comparison with placebo. Mean dryness VAS varied from 7.8 (1.8) to 6.2 (2.9) (P = 0.0021). There was no change in salivary flow or Schirmer's test [65]. A phase III trial is yet needed to further explore the relevance of belimumab in pSS. The efficacy of belimumab in SSc has been explored in a phase II trial with skin fibrosis evaluated by mRSS as primary outcome, showing no statistical difference between placebo and active therapy on this parameter [66]. Sicca symptoms were not evaluated in this study. A phase II trial evaluating the relevance of the combination of rituximab with belimumab in diffuse cutaneous SSc is currently ongoing (NCT03844061). The evaluation of sicca syndrome is not listed among the secondary outcome measures of this trial, suggesting that this frequent manifestation of SSc is an overlooked issue despite its impact on QoL.
The impact of autologous adipose tissue injections on sicca symptoms among other MHISS parameters was evaluated in a single centre open-label study. Fourteen SSc patients with facial handicap (MHISS ≥20) were included. A mean decrease in the MHISS score of 10.7 points was observed at 6 months in comparison with baseline (P < 0.001). Regarding secondary outcomes, an improvement of the sicca syndrome related handicap was suggested by a reduction of VAS for handicap related to dry mouth of 57.7% at 3 months (P < 0.001) and 53% at 6 months (P = 0.003) [67]. At 3 and 6 months after procedure, results from a self-administrated questionnaire evaluating xerostomia (the Xerostomia Inventory score) also significantly improved. Randomized controlled trials are needed to confirm these promising results.
Unmet needs and research agenda
There are still numerous unsolved questions and issues regarding sicca symptoms in patients with SSc, from the understanding of the specific pathogenesis to the assessment of the impact of therapeutics on sicca symptoms in SSc patients. Table 2 provides an overview of the main unmet needs and suggests a list of questions and approaches that may be added to the research agenda for the future.
Unmet needs and research agenda on SSc-related sicca symptoms
| Field | Research questions | Potential approaches |
|---|---|---|
| Pathogenesis | What are the sub-populations involved in the pathogenesis of sicca syndrome in SSc patients, including adaptive immunity (B cells, T cells), innate immunity (macrophages), glandular epithelial cells and fibroblasts? | Identification of new subpopulations using new omics technologies such as single cell RNA sequencing for SSc, pSS and overlap of pSS with SSc patients |
| Are there differences between SSc, pSS and overlap of pSS with SSc patients in terms of major contributing cell sub-populations, suggesting that therapeutic targets may differ between these sub-groups of patients? | ||
| Diagnosis and severity assessment | What is the contribution of US evaluation to the diagnosis and assessment of major salivary glands in SSc patients with sicca symptoms? | Comparison of US parameters with histological findings in SSc, pSS and overlap of pSS with SSc patients |
| Are there differences between SSc-related sicca symptoms and overlap with pSS in terms of US evaluation and are these differences associated with different histological patterns in minor salivary glands? | ||
| Clinical assesment | Are PROs currently used in patients with pSS adapted for sicca syndrome in SSc? | Evaluation of the psychometric properties of PROs assessing sicca symptoms in observational cohorts of patients with SSc |
| Are new PROs needed? | ||
| Therapeutics | Impact of new therapeutics on sicca symptoms in patients with SSc (anti-fibrotic drug such as nintedanib, B cell targeting therapies including rituximab or belimumab) | Inclusion of sicca symptoms as exploratory outcomes in future RCTs |
| Field | Research questions | Potential approaches |
|---|---|---|
| Pathogenesis | What are the sub-populations involved in the pathogenesis of sicca syndrome in SSc patients, including adaptive immunity (B cells, T cells), innate immunity (macrophages), glandular epithelial cells and fibroblasts? | Identification of new subpopulations using new omics technologies such as single cell RNA sequencing for SSc, pSS and overlap of pSS with SSc patients |
| Are there differences between SSc, pSS and overlap of pSS with SSc patients in terms of major contributing cell sub-populations, suggesting that therapeutic targets may differ between these sub-groups of patients? | ||
| Diagnosis and severity assessment | What is the contribution of US evaluation to the diagnosis and assessment of major salivary glands in SSc patients with sicca symptoms? | Comparison of US parameters with histological findings in SSc, pSS and overlap of pSS with SSc patients |
| Are there differences between SSc-related sicca symptoms and overlap with pSS in terms of US evaluation and are these differences associated with different histological patterns in minor salivary glands? | ||
| Clinical assesment | Are PROs currently used in patients with pSS adapted for sicca syndrome in SSc? | Evaluation of the psychometric properties of PROs assessing sicca symptoms in observational cohorts of patients with SSc |
| Are new PROs needed? | ||
| Therapeutics | Impact of new therapeutics on sicca symptoms in patients with SSc (anti-fibrotic drug such as nintedanib, B cell targeting therapies including rituximab or belimumab) | Inclusion of sicca symptoms as exploratory outcomes in future RCTs |
PROs: patient reported outcomes; pSS: primary Sjögren’s syndrome; RCT: randomized controlled trial.
Unmet needs and research agenda on SSc-related sicca symptoms
| Field | Research questions | Potential approaches |
|---|---|---|
| Pathogenesis | What are the sub-populations involved in the pathogenesis of sicca syndrome in SSc patients, including adaptive immunity (B cells, T cells), innate immunity (macrophages), glandular epithelial cells and fibroblasts? | Identification of new subpopulations using new omics technologies such as single cell RNA sequencing for SSc, pSS and overlap of pSS with SSc patients |
| Are there differences between SSc, pSS and overlap of pSS with SSc patients in terms of major contributing cell sub-populations, suggesting that therapeutic targets may differ between these sub-groups of patients? | ||
| Diagnosis and severity assessment | What is the contribution of US evaluation to the diagnosis and assessment of major salivary glands in SSc patients with sicca symptoms? | Comparison of US parameters with histological findings in SSc, pSS and overlap of pSS with SSc patients |
| Are there differences between SSc-related sicca symptoms and overlap with pSS in terms of US evaluation and are these differences associated with different histological patterns in minor salivary glands? | ||
| Clinical assesment | Are PROs currently used in patients with pSS adapted for sicca syndrome in SSc? | Evaluation of the psychometric properties of PROs assessing sicca symptoms in observational cohorts of patients with SSc |
| Are new PROs needed? | ||
| Therapeutics | Impact of new therapeutics on sicca symptoms in patients with SSc (anti-fibrotic drug such as nintedanib, B cell targeting therapies including rituximab or belimumab) | Inclusion of sicca symptoms as exploratory outcomes in future RCTs |
| Field | Research questions | Potential approaches |
|---|---|---|
| Pathogenesis | What are the sub-populations involved in the pathogenesis of sicca syndrome in SSc patients, including adaptive immunity (B cells, T cells), innate immunity (macrophages), glandular epithelial cells and fibroblasts? | Identification of new subpopulations using new omics technologies such as single cell RNA sequencing for SSc, pSS and overlap of pSS with SSc patients |
| Are there differences between SSc, pSS and overlap of pSS with SSc patients in terms of major contributing cell sub-populations, suggesting that therapeutic targets may differ between these sub-groups of patients? | ||
| Diagnosis and severity assessment | What is the contribution of US evaluation to the diagnosis and assessment of major salivary glands in SSc patients with sicca symptoms? | Comparison of US parameters with histological findings in SSc, pSS and overlap of pSS with SSc patients |
| Are there differences between SSc-related sicca symptoms and overlap with pSS in terms of US evaluation and are these differences associated with different histological patterns in minor salivary glands? | ||
| Clinical assesment | Are PROs currently used in patients with pSS adapted for sicca syndrome in SSc? | Evaluation of the psychometric properties of PROs assessing sicca symptoms in observational cohorts of patients with SSc |
| Are new PROs needed? | ||
| Therapeutics | Impact of new therapeutics on sicca symptoms in patients with SSc (anti-fibrotic drug such as nintedanib, B cell targeting therapies including rituximab or belimumab) | Inclusion of sicca symptoms as exploratory outcomes in future RCTs |
PROs: patient reported outcomes; pSS: primary Sjögren’s syndrome; RCT: randomized controlled trial.
Conclusion
Although overlap with pSS is only reported in <20% of patients with SSc, the prevalence of subjective sicca symptoms is much higher, since almost 80% of SSc patients may suffer from dry eyes or dry mouth. Although SSc patients with pSS tend to have a milder phenotype regarding visceral manifestations such as ILD or PAH, the proper diagnosis of overlap with pSS in SSc may still be important considering the higher risk of lymphoma in this subpopulation [55]. Beyond the association with pSS, histological findings suggest that SSc-related fibrosis of minor salivary glands may participate in specifically explaining this high prevalence of sicca syndrome in SSc. The specific relevance of non-invasive diagnostic instruments such as US evaluation of major salivary glands is yet to be determined in scleroderma patients.
Despite its high prevalence and its detrimental impact on quality of life, sicca syndrome is still poorly explored in SSc, notably since sicca symptoms are rarely included as a secondary outcome measure in recent randomized controlled trials (RCTs). Sicca syndrome may not be used as a primary outcome measure in SSc trials considering the importance of other manifestations of the disease and considering the disappointing results of recent RCTs using sicca symptoms as their primary outcome in pSS. However, there is a growing interest for combined response indices both in pSS and in SSc [68–71]. Including sicca symptoms among the parameters of such combined indices in SSc RCTs may participate in highlighting this neglected issue. To that extent, although it is not an index designed for RCTs per se, the Scleroderma Clinical Trials Consortium Damage Index has included sicca syndrome among its parameters [72]. Such an initiative may represent a first step to acknowledge the importance of this neglected issue in patients with SSc.
Acknowledgements
F.Z. and A.L. wrote the first draft of the manuscript, F.R., L.C., C.C., S.E.M., N.B., P.J., G.C. and A.L., corrected and added substantial modifications to the manuscript.
Funding: No specific funding was received from any bodies in the public, commercial or not-for-profit sectors to carry out the work described in this article.
Disclosure statement: F.Z., F.R., L.C., C.C., S.E.M., N.B., G.C. and A.L. report no conflict of interest. P.J. received speaking fees from Actelion Pharmaceuticals Ltd and Bayer (<€10 000 each) outside of the current study.
Data availability statement
Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.
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